1. Field of the Invention
This invention relates to the use of doxazosin or a pharmaceutically acceptable acid addition salt thereof for retarding the development of arterial disease in mammals. More specifically, it relates to a method for suppressing fibrosis and lipid deposition of developing atherosclerotic plaques and reducing atherosclerotic plaque involvement in mammals having atherosclerosis by administering to said mammals doxazosin or a pharmaceutically acceptable acid addition salt thereof.
2. General Background
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease has been described in detail by Ross and Glomset in New England Journal of Medicine 295, 369-377 (1976). The earliest stage in this sequence is the formation of "fatty streaks" (plaques) in the carotid, coronary and cerebral arteries and in the aorta. These, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion" which accounts for the the arterial occlusion and tendency toward mural thrombosis and arterial muscular spasm that characterize advanced atherosclerosis.
Statistical evidence suggests that hyperlipidemia and hypertension are primary risk factors in causing atherosclerosis. Treatment of atherosclerosis is, therefore, approached by attempts to control hypertension and hyperlipidemia by dietary or pharmacological means. Some success has been achieved in reducing the incidence and severity of atherosclerosis by strict adherence to a prudent diet, by lowering plasma lipids with drugs or with ileal bypass surgery and by lowering systemic blood pressure with diet or drugs. However, coronary heart disease remains a threat, even to individuals striving to control their risk factors. It has been speculated that every individual in the United States has some degree of atherosclerosis. This fact, along with the high associated mortality and the inadequacy of the present treatment methods, establishes the need for anti-atherosclerotic agents.
Doxazosin, 4-amino-2-[4-(1,4-benzodioxan-2- carbonyl)piperazin-1-yl]-6,7-dimethoxyquinazoline, its pharmaceutically acceptable acid addition salts and their use as regulators of the cardiovascular system, particularly in the treatment of hypertension are described in U.S. Pat. No. 4,188,390.
The use of trimazosin, 2-hydroxy-2-methylpropyl-4-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-1-pip erazinecarboxylate, or a pharmaceutically acceptable acid addition salt thereof as an agent for retarding the development of atherosclerosis by suppressing fibrosis of atherosclerotic lesions is disclosed and claimed in U.S. Pat. No. 4,582,832.
Prazosin, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine, and its pharmaceutically acceptable acid addition salts as well as trimazosin and its pharmaceutically acceptable acid addition salts, are disclosed in U.S. Pat. No. 4,130,647 as antihypertensive agents useful in treating congestive heart failure and ischemic heart disease.
The use of prazosin among other vasodilators in the prevention of renal failure and damage is disclosed in U.S. Pat. No. 4,361,564. Further, U.S. Pat. No. 4,532,135 discloses the use of trimazosin, doxazosin and prazosin among other vasodilators in preventing renal failure through reduction of plasma lipid levels, a risk factor in renal failure.
However, in spite of the above-mentioned uses for doxazosin and its salts, the use of trimazosin and prazosin as antihypertensive agents and as agents for prevention of renal failure and the use of trimazosin as an anti-atherosclerotic agent, there was, prior to the time of the present invention, no report of the use or intent to use doxazosin or its salts for retarding the development of atherosclerosis, nor any appreciation of its role, or that of its pharmaceutically acceptable acid addition salts in achieving said desirable goal.